17beta-ethers of delta 4 9 11-gonatrienes and compositions containing them

ABSTRACT

WHEREIN A REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF OXYGEN, DI-LOWER-ALKOXY AND LOWER ALKYLENE DIOXY; R REPRESENTS ALKYL HAVING FROM 1 TO 4 CARBON ATOMS; R1 REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL; AND R2 REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF SUBSTITUTED AND UNSUBSTITUTED PHENYL, CYCLOHEXYL, CYCLOHEXENYL AND CYCLOHEXADIENYL. THESE COMPOUNDS HAVE A PARTICULARLY LONG-LASTING AND PERSISTENT ANABOLISANT AND ANDROGENIC ACTIVITY, ON SUBCUTANEOUS ADMINISTRATION.   3-(A=),7-R1,13-R,17-(R2-CH2-O-)GONA-4,9,11-TRIENE   THIS INVENTION RELATES TO 17B-ETHERS OF $4,9,11-GONATRIENES OF THE FORMULA

United States Patent O 3,629,244 17B-ETHERS OF A -GONATRIENES AND COMPOSITIONS CONTAINING THEM Germain Costerousse, Montrouge, and Jean-Claude Gasc, Bondy, France, assignors to Roussel-UCLAF, Paris, France No Drawing. Continuation-impart of application Ser. No. 628,273, Apr. 4, 1967. This application Aug. 13, 1969, Ser. No. 850,346 Claims priority, application France, July 8, 1966, 68,751; Feb. 15, 1967, 95,053 Int. Cl. C07c 173/00 US. Cl. 260239.55 16 Claims ABSTRACT OF THE DISCLOSURE This invention relates to 17fl-ethers of Mfl -gonatrb enes of the formula wherein A represents a member selected from :the group consisting of oxygen, di-lower-alkoxy and lower alkyl ene dioXy;

R represents alkyl having from 1 to 4 carbon atoms;

R represents a member selected from the grou consisting of hydrogen and lower alkyl; and

R represents a member selected from the group consisting of substituted and unsubstituted phenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. These compounds have a particularly long-lasting and persistent anabolisant and androgenic activity, on subcutaneous administration.

IPRIOR APPLICATIONS This application is a continuation-in-part of the copending application Ser. No. 628,273, filed Apr. 4, 1967, now abandoned.

OBJECTS OF THE INVENTION An object of the present invention is the obtention of 17fl-ethers of A -gonatrienes of the formula wherein A represents a member selected from the group consisting of oxygen, di-lower-alkyloxy and lower alkylene dioxy;

R represents alkyl having from 1 to 4 carbon atoms;

R represents a member selected from the group consisting of hydrogen and lower alkyl;

R represents a member selected from the group consisting of substituted and unsubstituted phenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl.

3,629,244 Patented Dec. 21, 1971 DESCRIPTION OF THE INVENTION The present invention relates to the 17B-ethers of A -gonatrienes of the general Formula I R OCHg-RZ wherein A represents an oxygen atom or a ketal radical,

R represents an alkyl radical having from 1 to 4 carbon atoms;

R represents a cyclic hydrocarbon radical, substituted or unsubstituted, saturated or unsaturated;

R represents a hydrogen atom or a lower alkyl radical.

The 17,8-cyclic hydrocarbon-methoxy compounds f the general Formula I possess interesting physiological properties; in particular, they possess an anabolisant action. Moreover, they are endowed with a significant androgenic activity. Particularly, the compounds, when administered in an oily solvent, are active on the proteidic metabolism in a long lasting and persistent manner over a period of at least thirty days.

In a general manner, the great advantage of the 17B- cyclic ethers of the A gonatrienes of the general Formula I lies in the fact that they are active over long periods of time, administered by a single injection in an oily solvent.

The process for the preparation of the l7B-cyclic ethers of the A -gonatrienes of the general Formula I is accomplished according to classical methods. Advantageous results are obtained by utilizing etherification processes particularly adapted for the obtention of the categories of the desired structure. Of course, these particular etherification processes represent part of the present invention.

The processes for the preparation of the 17/3-cyclic ethers of the A -gonatrienes of the general Formula I are characterized in that an etherification is effected in a known manner such as by the action of a halomethylcyclic hydrocarbon, wherein the cyclic hydrocarbon radical is substituted or unsubstituted, saturated or unsaturated, on a monoor divalent metal derivative of a 3metal-A -gonatriene-17/3-ol, and, if desired, the 3-ketal-17-ether formed is subjected to an acid hydrolysis to obtain the corresponding 3-keto compound.

The starting materials for the etherification reaction are A -gonatriene-17,8-ols of the formula wherein A is a ketal group and R and R have the aboveassigned values may be prepared by the method described in British patent specification No. 1,069,709 and other published literature indicated in the examples.

The substituent R of general Formula I can be a cyclic hydrocarbon radical, substituted or unsubstituted, saturated or unsaturated. Preferably, the 175-cyclic ethers of the A -gonatrienes have the following Formula II wherein A is a member selected from the group consisting of oxygen and lower alkylene dioxy, such as ethylenedioxy.

R is an alkyl having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, etc.

R is a member selected from the group consisting of phenyl, lower alkylsulfonylphenyl, lower alkylphenyl halophenyl, lower alkoxyphenyl, cyclohexy and cycohexenyl, such as p-methylsulfonylphenyl, 2,4',6-trimethylphenyl, p-chlorophenyl, p-methoxyphenyl, cyclohex-1'-enyl, etc.; and

R is a member selected from the group consisting of hydrogen and methyl, such as 7oc-methyl.

The 17fi-cyclic ethers of the A -gonatrienes of the above Formula I possess in particular an important anabolisant and androgenic action. When they are administered, preferably in an oily solvent such as olive oil containing benzyl alcohol, they have an extremely longlasting effect. By tagging with a radio-active element, it has been ascertained that on injection, the compounds remain at the point of injection and persist at this point for more than thirty days. This allows a slow and even dissemination of the products into the blood stream and gives a controlled long time anabolisant and androgenic action.

The products may be utilized for the treatment of disturbances of proteidic anabolism, asthenia, thinness, osteoporosis, andropause, senescence, retardation of the consolidation of fractures, metabolic disturbances from prolonged corticotherapy, adiposo-genital syndrome, functional meno-metrorrhagia, fibroma endometriosis and as a cicatrization agent in the treatment of varicose ulcers.

The products of the invention may be administered by injection in warm-blooded animals transcutaneously. They are prepared in the form of injectable solutions or suspen sions in the customary manner.

The useful dosology of the l7fl-cyclic ethers of the A -gonatrienes of the invention is controlled between 15 to 100 mg./ kg. in the warm-blooded animal depending on the frequency of administration.

The following examples serve to characterize the invention. However, it is to be understood, that they do not limit the scope of the invention in any manner.

EXAMPLE 1 1713-benzyloxy-A -estratriene-3-0ne (I, A=O, R=CH R =H and R =phenyl) (A) Preparation of 3-ethylenedioxy-l7fl-benzyloxy- A' -estratriene CHr-O C Hz- R=CH R H and R phenyl).

Over a period of one hour, at a temperature of 60 C., 3.144 gm. of 3-ethylenedioxy-A -estratriene-175-01 and 1.2 gm, of sodium hydride in Vaseline oil were heated in 45 cc. of tetrahydrofuran. Then 4.75 cc. of benzyl bromide were added and the mixture was held at reflux for three hours. Thereafter, the reaction mixture was returned to the temperature of 20 C. and poured into a water-ice mixture. Next, the reaction mixture was extracted with methylene chloride. The methylene chloride phases were washed with water and dried over sodium sulfate. 2 cc. of triethylamine were added to the organic phase which was then evaporated to dryness. The residue obtained was taken up in 45 cc. of petroleum ether. The solution was evaporated to dryness, and 7.2 gm. of raw product were recovered, which was purified by chromatography and recrystallization from isopropanol. 2.144 gm. of 3-ethylenedioxy-17/3-benzyloxy-A -estratriene were obtained. The product occurred in the form of beige colored crystals, soluble in alcohol and chloroform, and insoluble in water. It had a melting point of 95 C.

Ultraviolet spectra (in ethanol):

Inflection toward 267 mu E}? =386 Inflection toward 280 m E}";,,, =702 Max. at 289-290 m E}Z ,=930 or e=37,650

Inflection toward 300 mu E}",,, =760 Inflection toward 336 m E}Z" ,=9.7

This compound is not described in the literature.

(B) Preparation of 3-ethylenedioxy-A -estratriene- 176-01, the starting compound.

3.7 gm. of 3-ethylenedioxy-A -estratriene-l7-one, described in the published Dutch patent application No. 6607609, were introduced into 55 cc. of anhydrous methanol. Next, in small fractions, 1.150 gm. of sodium borohydride were added. The mixture was agitated for 15 minutes and diluted with methylene chloride. The organic solution was washed twice with water, dried and concentrated to dryness under reduced pressure. The residue was crystallized from methanol containing 1% of pyridine. In this manner 2.8 gm. of 3-ethylenedioxy-A estradiene-17 S-ol were obtained, having a melting point of C.

Ultraviolet spectra (in ethanol):

Inflection toward 268 m l (e=16,300) Inflection toward 280 m (e=29,300) Max. at 289-290 Ill/L (e=38,600) Inflection toward 299 m (e='31,800) Inflection toward 340 III/L (6 104) This product is not described in the litherature.

(C) Preparation of 17/3-benzyloxy-A -estratriene-3- one.

2.08 gm. of 3-ethylenedioxy-l7B-benzyloxy-A -estratriene were dissolved in 50 cc. of methanol, 1 cc. of water and 1 cc. of acetic acid. The solution was poured into a water-ice mixture and was extracted with methylene chloride. The organic phases were washed first with a saturated aqueous solution of sodium bicarbonate, then with Water, dried over sodium sulfate and evaporated to dryness. 1.865 gm. of a raw 17 6-benzyloxylated derivative were recovered, which was then purified by recrystallization by heating and cooling from isopropanol, thus obtaining 1.525 gm. of 17fi-benzyloxy-A -estratriene-3-one.

The product occurred in the form of pale yellow crystals, soluble in chloroform, and insoluble in water. The melting point was 134 C. with a specific rotation (c=0.5% in methanol).

A/zalysis.C H O (percent): molecular weight =360.47. Calculated (percent): C, 83.29; H, 7.83. Found (percent): C, 83.0; H, 7.8.

Ultraviolet spectra (in ethanol): From these results, it can be noted that 17,3-benzyloxy- Max. M 238 In Eli-fin :175 A -estratriene-3-one possesses, given orally, an an- I fi 2 m abohsant and androgenlc activity appreciably equal to n ection toward 56 m E 100 that of l7a-methyl-A -estratriene-17fi-ol-3-one. Ad- Infiection toward 260 m Ef =1OO 5 ministered subcutaneously, the product studied is also as Infiection toward 284 mu Egan: 125 anabolisant as the comparison product, while being slight- Max. at 342343 m Ei'%,., =805 or e=29,000 1y less androgemc' This compound is not described in the literature. (D) Pharacological study.Determination of the 10 anabolisant and androgenic activities:

The tests were eifected according to the technique employed by Hershberger (Proc. Soc. Exp. Biol. Med. 1953, (1, R=CHb 31:13 and 83, 175), slightly modified. The test was conducted on male castrated rats, three and a half weeks old. The rats A Preparation f 3- thyl di y 17p-( .m th 1f EXAMPLE 2 1 7 B- p-methylsulfonyl -b enxyloxy-A estratriene-3-one were treated, beginning the day following the castration, n l) b 1 4,9,lL t i over a period of ten days, every day with the exception of the sixth day. Then they were sacrificed on the eleventh CH2O day, 22 to 26 hours after the last administration. (I, 11:0 H 17 :1; and R,=-SO;CHQ

The animals were sub ected to autopsy and the organs CH 0 of interest were removed and weighed, in particular the r levator ani for the study of the anabolisant action, the 5 gm of 3 ethy1enedioXy A4,sanestratrigng1754)} prostate glanfi and the Semmal Veslcles for the Study of were dissolved in 37 cc. of tetrahydrofuran and 0.95 gm. the androgemc effect- I of sodium hydride in vaseline oil were added thereto.

B' Y i s uflllzed In an The mixture was heated to 45 C. for a period of fortyy solutlon. was admlnlstered Orally at dally doses of five minutes. Thereafter, under agitation and an atmo- 10 10 10 sphere of nitrogen, 6.21 gm. of (p-methylsulfonyD-benzyl 47X, 207 and 100 X bromide were added thereto. The mixture was agitated for a period of twenty-three hours, refrigerated and the excess (total doses of 200 and 1 mg. given in nine adminsodium hydride was destroyed by ice water. The mixture istrations over a period of ten days). The test was effected was extracted with methylene chloride. The organic phases in comparison with the 17ot-methyl-A -estratriene-175- were washed with water until neutral and evaporated to ol3-0ne administered under the same experimental condryness under vacuum. The residue was subjected to ditions and at the same doses. 35 chromatography on silica and eluted with a mixture of The results are summarized in Table I. benzene and ethyl acetate (7:3).

TABLE I Fresh Seminal Prostate Daily levator vesicles, gland Lots dose ani, mg. mg. mg.

Control 0 15 1 5 4 7 3 17,5benzyloxy-B -estratricne-3-one 1 x 10 18 7 I 85 16 0 20 0 32 6 10 4 22.0 1007 .50 49 2 46.9 67.8

17a-methyl-A -"-estratriene17B-ol-3-one 4 b0 21 0 9 S 23.7 207 50 31.4 29.8 44.0 100'yX1)0 40.6 81.9 77. 9

In a second test, the studied product was administered 1.94 gm. of 3-ethylenedioxy-17;3-(p-methylsulfonyl)- subcutaneously at daily doses of benzyloxy-A -estratriene (yield-40%) were obtained which were utilized as such in the next step. 107 LQ and This compound is not described in the literature.

9 9 (B) Preparation of 17p-(p-methylsulfonyl)-benzyloxyin a solution of olive oil admixed with 5% of benzyl A43u'estramene'3'onealcohol. This product was compared with the 17,8-acetoxyof yf '(P' Y y A estratriene-3-one administered under the same exbenzyloxy-A -estratriene were dlssolved in 67 cc. of perimental conditions and at the same doses. methanol and 9.4 cc. of water and 1 gm. of citric acid In Table II the results obtained are summarized. was added thereto. The reaction mixture was agitated for TABLE II Fresh Seminal Prostate Daily levator vesicles, gland, Lots dose ani, mg. mg. mg.

Control 0 15. 1 5. 4 7. 3

l7l3-benzyloxy-A -cstratrienc-3-0ne IO' XO 25.9 7.5 16.1 1007X1)0 60. 6 68. 0 71. 7

17fi-acctoxy-A --"-estratricnc-3-onc 107 {130 38.1 23.0 30.3 y 0 52. 4 99. 9 91. 3

forty minutes under an atomsphere of nitrogen and then poured into water. The aqueous mixture was extracted with methylene chloride. The organic phases were washed with water until neutral, dried over sodium sulfate and evaporated to dryness under vacuum. The residue was subjected to chromatography on silica and eluted with a mixture of benzene and ethyl acetate (7:3). 720 mgm. of raw product were recovered which was purified by recrystallization from methylene chloride and isopropyl ether. 690 mgm. of 17fl-(p-methylsulfonyl)-benzyloxy-A -estratriene-3 one (yield-39%) were obtained.

The compound occurred in the form of colorless needles and was soluble in ethanol and chloroform and insoluble in water. It had a melting point of 180.5 C. and a specific rotation [a] =+48i2 (c.=0.5% in ethanol).

Analysis.--C H O S (percent) molecular weight 2438.59. Calculated: C, 71.20; H, 6.89; S, 7.31. Found (percent): C. 71.3; H, 6.9; S, 7.3.

Ultraviolet spectra (in ethanol):

Max. at 226 m Ei'fi =365 Max. at 267 mu El?m.=l01

Max. at 273 III); E}f =102 Max. at 341 m E{",? =676 r e=29,600

This compond is not described in the literature.

EXAMPLE 3 17fl-(2,4,6-trirnethyl)-benzyloxy-A -estratriene- 3-one (I, A=O, R=CH3, R1=H and R2= CH3) (A) Preparation of 3-ethylenedioxy-17/3-(2,4',6-trimethyl)-benzyloxy-A -estratriene CH3 CH -O (I, A: R=CH3, R1=H and R,=-

A mixture of 1.3 gm. of sodium hydride in Vaseline ,oil, 26 cc. of tetrahydrofuran and 6.5 cc. of dimethylsulfoxide was agitated for a period of fifteen minutes at room temperature. A solution of 1 gm. of 3-ethylenedioxy-A estratriene-1718-ol in 30 cc. of tetrahydrofuran was added thereto and the mixture was agitated for a period of thirty minutes. Thereafter, 2.65 gm. of 2,4,6-trimethylbenzyl chloride were added. The reaction mixture was agitated for a period of fifteen hours at room temperature under an atmosphere of nitrogen. The excess of sodium hydride was then destroyed by the addition of ice. Water was added and the mixture was extracted with ethyl ether. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography over silica gel and eluted with a mixture of cyclohexane and ethyl acetate (9:1) containing 0.2% of triethylamine.

893 mgm. of raw compound were recovered, which was dissolved in 9 cc. of methanol and 9 cc. of benzene and filtered. The benzene was evaporated from the solution while replacing it with methanol. Thereafter, the solution was concentrated until the start of crystallization and iced. 569 mgm. of 3-ethylenedioxy-17,6-(2,4,6'-trimethyl)-benzyloxy-A -estratriene (yield-40%) were obtained.

The compound occurred in the form of a solid, colorless product, soluble in benzene and ethyl ether, slightly soluble in methanol, and insoluble in water, melting as 146 C.

Alzalysis.C H O (percent): molecular weight =446.60. Calculated: C, 80.68; H, 8.58. Found (percent): C, 81.2; H, 8.7.

This compound is not described in the literature.

(B) Preparation of 17B-(2',4',6-trimethyl)-benzyloxy- A -estratriene-3-one.

550 mgm. of 3-ethylenedioxy-17/3-(2',4',6'-trimethyl)- benzyloxy-A' -estratriene were placed in suspension in 17 cc. of methanol and 2.9 volumes of water. The suspension was agitated for a period of fifty minutes at room temperature and 290 mgm. of citric acid, then 11.6 cc. of acetone were added. The reaction mixture was agitated for a period of thirty minutes. 15 cc. of water were added and the mixture was filtered. Crystallization was induced by scratching. The crystals were vacuum filtered and dried under vacuum.

404 mgm. of -(2',4,6-trimethyl)-benzyloxy-A estratriene-3-one were obtained in the form of a pale yellow, solid product. The product is soluble in ethanol, chloroform, ethyl ether and benzene, slightly soluble in methanol, and insoluble in water. It melts at 117 C. and its specific rotation [u] =+74i2 (c=0.5% in ethanol).

Analysis. C H O (percent): molecular weight =402.55. Calculated: C, 83.54; H, 8.51. Found (percent): C, 83.3; H, 8.5.

LR. Spectra (chloroform) shows: Presence of the Itrienone Presence of CO-C Presence of an aromatic ring at 1,614 cm.-

U.V. Spectra (ethanol):

Infleetion towards 239 m E}" ,=168

Inflection towards 270 mg E}",,,,=99

This compound is not described in the literature.

EXAMPLE 4 7ot-n1cthyl-l7fl-benzyloxy-A -estratriene-3-one (I, A=O, n=ou upon, and R (A) Preparation of 3,3-dimethoxy-7m-methyl-17fl-benzyloxy-A -estradiene.

5 gm. of 3,3-dimethoxy-7a-methyl-A -estradiene-17/3-ol were dissolved in 75 cc. of tetrahydrofuran under an atmosphere of nitrogen. The interior temperature was brought to +10 C. and 1.90 gm. of sodium hydride in Vaseline oil was added thereto. The mixture was agitated and heated for a period of thirty minutes at an interior temperature of 5254 C. Thereafter, 5.40 gm. of benzyl bromide were added and the mixture was agitated under an atmosphere of nitrogen for a period of seventeen hours at an interior temperature of 65 C. The mixture was poured into a mixture of water and ice, and extracted with methylene chloride. The organic phases were washed with water until neutral, dried over sodium sulfate and distilled to dryness under vacuum. The residue was subjected to chromatography on magnesium silicate and eluted with cyclohexane, then with methylene chloride.

2.17 gm. of 3,3-dimethoxy-7u-methyl-17B-benzyloxy- A -estradiene were obtained in the form of a solid, colorless product melting at 45 -50 C.

I.R. Spectra (chloroform) showed: Presence of aromatic ring Presence of COC Absence of OH This compound is not described in the literature.

The starting compound, 3,3 dimethoxy 7a methyl- A -estradiene-17fi-ol is described in the copending application Ser. No. 602,112, filed Nov. 29, 1966, now abandoned.

(B) Preparation of 70a methyl 17 8 benzyloxy- A -estradiene-3-one.

0.15. gm. of 3,3-dimethoxy-7u-methyl-17B-benzyloxy- A -estradiene were dissolved in 2 cc. of 95% acetic acid under agitation at room temperature. 0.3 cc. of water were added and the mixture was agitated for a period of one hour under an atmosphere of nitrogen. A further 2 cc. of water were added and the mixture was extracted with ether. The ethereal phases were washed with water, with an aqueous sodium bicarbonate solution, and again with water, and distilled to dryness under vacuum.

0.12 gm. of 7a-methyl-17,8-benzyloxy-A -estradiene-3-one were obtained, which was used as such in the next step.

This compound is not described in the literature.

(C) Preparation of 7a-methyl-11fl-hydroperoxy-17/3- benzyloxy-A -estradiene-3one.

1.51 gm. of 7a-methyl-17,8-benzyloxy-A -estradiene-3-one were dissolved in 100 cc. of ethanol containing 0.2 cc. of triethylamine at room temperature. A stream of oxygen was passed therethrough for a period of nineteen hours. The solvent was evaporated to dryness under vacuum at a low temperature. 1.60 gm. of 7amethyl 11B hydroperoxy 17,8 benzyloxy A estradiene-3-one were obtained, which was used as such in the next step.

This compound is not described in the literature.

(D) Preparation of 7a methyl 175 benzyloxy-A estradiene-l 1 ,B-ol-3 -.one.

1.60 gm. of 7ot-methyl-1lB-hydroperoxy-17/i-benzyloxy-A -estradiene-ilone were dissolved in 50 cc. of methanol at room temperature. 2.5 cc. of trimethyl phosphite were added. The mixture was agitated for a period of thirty minutes and poured into 500 cc. of water containing 3 cc. of a 30% hydrogen peroxide solution. Sodium chloride was added and the mixture was extracted with methylene chloride. The organic phases were washed with an aqueous solution of sodium chloride, dried and evaporated to dryness under vacuum. The residue was subjected to chromatography over silica and eluted with a mixture of benzene and ethyl acetate (4:6).

0.86 gm. of 7u-methyl-17,8-benzyloxy-A -estradiene- 11B-ol-3-one were obtained which was utilized as such in the next step.

I. R. Spectra (chloroform) showed:

Presence of OH at 3,590 Presence of dienone. Presence of aromatic ring at 1,496 Presence of COC U.V. Spectra (ethanol):

Max. at 233 mp Ett...=126 Max. at 299 my Eit...=466 or e=18,300

This compound is not described in the literature.

(E) Preparation of 7a-methyl-l7;3-benzyloxy-A estratriene-3-one.

0.86 gm. of 7a-methyl-17 8-benzyloxy-A -estradiene- 11fi-ol-3-one were dissolved in 50 cc. of methylene chloride and 3 cc. of acetonitrile were added thereto under agitation at room temperature. Thereafter, 0.6 cc. of a 56 B. perchloric acid solution were added while agitating for a period of two minutes thirty seconds and then the solution was poured into water. The mixture was agitated, the organic phase was separated and washed with water until neutral, and distilled to dryness. The residue was recrystallized from isopropyl ether. 0.80 gm. of raw product were recovered, which was subject to purification by chromatography on silica and elution with a mixture of benzene and ethyl acetate (7:3).

0.65 gm. of 7u-rnethyl-17B-benzyloxy-A -estratriene- 3-one were obtained in the form of a beige solid product, soluble in alcohols, ethyl ether and chlorinated solvents and insoluble in Water. It melted at 120 C. and had a specific rotation [a] =--20i4 (c=0.25% in ethanol).

Analysis.C H O (percent): molecular weight =374.50. Calculated: C, 83.38; H, 8.07. Found (percent): C, 83.2; H, 8.2.

U.V. Spectra (ethanolz) Max. at 238-239 m Elt...=172 Inflection towards 256 m E1 2 108 Max. at 269-270 mp 13%.: 106 Infieetion towards 282 m Elfi 116 Max. at 343344 m iZ ,=734 or e=27,500

This compound is not described in the literature.

EXAMPLE 5 13 /3-ethyl-17/3-benzyloxy-A -gonatriene-3-one A o, R: 011,011,, R1=H and R,=-)

(A) Preparation of 3ethylenedioxy-13,8-ethyl-17fi-benzyloxy-A -gonatriene GHQ-O 1.5 gm. of. 3-ethylenedioxy-13,8-ethyl-A -gonatriene- 176-01 were dissolved in 45 cc. of tetrahydrofuran and 420 mgm. of sodium hydride in vaseline oil were added. The reaction mixture was heated to 60 C. for a period of one hour and cooled. 3 cc. of benzyl bromide were added and the mixture was agitated for a period of sixteen hours at 60 C. The reaction mixture was brought to room temperature and 10 cc. of water were added. Thereafter the mixture was poured into water and extracted with ethyl ether. The ethereal phases were washed with water, then with an aqueous solution of sodium chloride, dried over magnesium sulfate and distilled to dryness under vacuum.

4.6 gm. of raw 3-ethylenedioxy-13,8-ethyl-17B-benzyloxy-A -gonatriene were obtained which was utilized as such in the next step.

This compound is not described in the literature.

The starting compound S-ethylenedioxy-13,8-ethyl- A -gonatriene-17/3-ol is described in British patent specification No. 1,069,709.

(B) Preparation of 13,8-ethyl-17fi-benzyloxy-A gonatriene-3-one.

4.6 gm. of 3-ethylenedioxy-BIB-ethyl-17B-benzyloxy- A -gonatriene were dissolved in cc. of methanol containing 10% water. 820 mgm. of citric acid were added and the reaction mixture was agitated for a period of one hour in an inert atmosphere at room temperature. The reaction mixture was then poured into Water and U.V. Spectra (ethanol):

Max. at, 237238 m E}Z,., =l07 Max. at 269 m E =97 1 cm. Max. at, 342 mu Ei =792 or e=29,700

This compound is not described in the literature.

(C) Determination of the anabolisant and androgenic activities of l3fi-ethyl-17fl-benzyloxy-A -gonatriene-3- one.

The tests were effected according to the technique described in Example I(D) above.

The tests were made both by oral administration as well as by subcutaneous administration.

(1) Oral administration 13B ethyl-17B-benzyloxy-A -gonatriene-3-one, utilized in a solution in olive oil, was administered orally at daily doses of 10 10 and 307x (total doses of 100 and 300 given in nine administrations over a period of ten days).

The results are summarized in Table III.

12 From these results, it can be noted that 13fl-ethyl-17B- benzyloxy-A -gonatriene-3-one possesses, when administered both orally and subcutaneously, an anabolisant and androgenic activity.

EXAMPLE 6 17,8-cycl0hexylmethoxy-A -estratriene-3-0ne CII C H -CH,

(A) Preparation of 3 ethylenedioxy 17fl-cycl0hexylmethoxy-A -estratriene.

3.9 gm. of sodium hydride were suspended in cc. of tetrahydrofuran and 18 cc. of dimethylsulfoxide at room temperature under an atmosphere of nitrogen. The mixture was agitated for 30 minutes, then 2.41 gm. of 3-ethylenedioxy-A -estratriene--01 were added, and the agitation was continued for 30 minutes. 7 cc. of cyclohexylmethyl bromide were added, and the mixture was agitated for 21 hours. Then 3.5 cc. of cyclohexylmethyl bromide were added and agitation was continued for 24 hours. Then a small quantity of water was added while agitating and maintaining the reaction mixture under an atmosphere of nitrogen and at a temperature below 20 C. The mixture was poured into water and extracted with ethyl ether. The ethereal extracts were washed with a 0.1 N sodium hydroxide solution, then with water, dried and evaporated to dryness. The residue was chromatographed over alumina, thus yielding 1.54 gm. of 3 ethylenedioxy 175-cyclohexylmethoxy-A estratriene which was used as such for the next step of the synthesis. The product is soluble in ethanol, chloroform, benzene and ethyl ether, and insoluble in water.

As far as is known, this compound is not described in the literature.

(B) 17 3-cyclohexylmethoxy-A -estratriene-3-one.

1.54 gm. of the compound obtained in the preceding TABLE III Fresh Seminal Prostate levntor vesicles, gland, Lots Daily dose ani, mg. mg. mg.

Control O 18. 5 5. 3 10. 9

1 0 13r3-ethy1-17p8-benzyloxy-A -gonatriene-El-one 10'yX9 24. 0 7. 8 13. 7

(2) Subcutaneous administration The studied product was administered subcutaneously at daily doses of in a solution of olive oil admixed with 5% of benzyl alcohol under similar conditions.

In Table IV the results obtained are summarized.

TABLE IV Presh Seminal Prostate levator vesicles, gland, Lots Daily dose ani, mg. mg. mg.

Controls O 22. 2 2. 6 6. 5

10 13fl-etl1yl-17B-bcuzyloxy-A -g0uatri0uc-3-one IOyXB- 24. 7 7. 5 20. 4

by filtration and washed with ice-cold pentane. There were obtained 507 mgm. of product, melting at 6570 C. The mother liquors were chromatographed over alumina and eluted with ethyl ether. The eluted product Analysis.-C H O Cl (percent): molecular weight =394.95. Calculated: C, 76.02; H, 6.89; Cl, 8.97. Found (percent): C, 76.0; H, 7.0; CI, 9.0.

Ultraviolet spectra (ethanol):

was recrystallized from pentane, thus yielding a second 5 l7 crop of 175 mgm, of a product identical with that M 2214322 u im.= obtained above. f Inflection towards 224 In E}'Z? =350 For purpose of purification, the combined crops 0 1% product were dissolved in ethyl ether, treated with carbon Inflectlon towardslgg6 177 black, chromatographed over alumina, eluted with ethyl at 269 E1cm-=99 ether and the collected ethereal solutions were evaporated Max. at 340 mu E{ ,=759 or e=30,000 y i resldule was glssolzed f fi i fi This compound is not described in the literature. g i: 2 51 pen p f t 6 so zgg 1713 p methoxybenzyloxy A estratriene-El-one lce'coo or m1 i e preclpl a e was in the form of pale yellow crystals having a melting point by filtration, washed with ice-cold pentane and dried, thus 5 s o o ield'n 17 c clohex lmethox -A -estratriene-3-one of 97 and specific rotanon [061D +44 :2 y g la y a y ("c.=0.5% in ethanol containing 1% of triethylamine). melting at 6668 C., and having a specific rotation I 370+? 467 th 1 t The product is soluble in acetone, ethanol and methylene $2 3.79} m 6 am) con ammg chloride and insoluble in water 0A n 15378;; amneH. O (prcenty molecular Wei 20 AnalysiS.C I-I O (percent): molecular weight 34 2 a a =366.52. Calculated (percent): 0, 81.92; H, 9.35. Found jgg-j f gg Found (Percent) (percent): C, 82.1;H, 9.6.

Infrared spectra: Presence of the trienone. Ultravlolet Spectrum! 5 Presence of an aromatic ring substituted by a betat 23 myL Ei j 5g eroatom at 1613 and 1507 cmr Infiection toward 270 m E} 'Z ,=93 Ultraviolet spectra: Max. at 314 my E}'? =783 or e=28,700 at 7 lZm= Infiection towards 240 m Ei g =172 As far as is known, this compound is not described in Illflection towards 275 111M lla-= the literature. Max. at 281 m E}" =14O (C) Pharmacological S tudy.Determination of ana- Max. at 340%41 mp. Eizum=7s5 or =30I650 bolic and androgenic activities. 35

The tests were conducted as in Example I(D) above. E T g IS 19 idescllfllbed i ii t 17,8 cyclohexylmethoxy A estratriene 3 one t 5 (eye 9 enyd) me :f'Ai d es was administered orally at daily doses of Is compoun Is not e m t 6 literature.

0 0 40 EXAMPLE 7.--PHARMACOLOGICAL TESTS 10 X and 100 X- 7 9 7 9 (A) Determination of the retarded anabolisant and androgenic actions (total doses of 0.1 and 1 mgm. given in 9 adniinistra- Sakamoto test: The determination of the retarded effect tions over a period of 10 days). was made according to the technique of Sakamoto et al. The results are summarized in Table V. (Proc. Soc. Exp. Biol. Med. 76, 406 [1951]). Male rats,

TABLE V Fresh Seminal Prostate levator vesicles, gland, Lots Daily dose anl, mg. mg. ll mg.

Controls 0 15. 4 4. s 10. 4

i0 17B-cyclohexylmethoxy-A -estratriei1e-3-0ne 107X? 25. 6 7. 1 13. 6

i0 IOO'YXF 5.4 28. r 35.9

These results show the studied compound possesses a castrated at the age of four and a half weeks, received marked anabolic and androgenic activity when admina single subcutaneous injection of the product at the age istered orally. of seven and a half weeks. Thereafter, they were sacri- In an analogous manner, the following 1713 cyclic ficed various days after the injection as is indicated in ethers of A -gonatrienes of the general Formula I Table VI. were obtained: The animals were subjected to autopsy after their 173 p chlorobenzyloxy A estratriene 3 one sacrifice and the organs of interest were separated and in the form of a colorless solid having a melting point of weighed, in particular, the seminal vesicles and prostate 113 C. and a specific rotation [a] =+54.5i1.5 gland for the determination of the androgenic efiect and (ethanol). The product is soluble in ether, benzene and the levator ani for the study of the myotrophic action. methylene chloride, slightly soluble in alcohols and 5 1713 benzyloxy A estratriene 3 one was adinsoluble in water.

ministered at doses of 2 mg. and 10 mg. per animal.

15 17,8 cyclohexylmethoxy A estratriene 3 one was administered at a dose of 10 mg. per animal. 7a methyl 17B benzyloxy A estratriene-3-one was administered at a dose of 10 mg. per animal.

16 Expression of the results With the adsorption spectra, the presence of the product is shown when the difference between the control versus the treated absorptions presents a maximum in the neigh- TABLE VI Fresh Seminal Day of Dosage, levator vesicles, Prostate, sacrifice Treatment mg ani, mg. mg. mg.

{Control 34. 3 6. 10. 6 17fi-benzyloxy-A m- -estratriene-3-or 2 70. 9 36. 6 36. 0 111. 8 245. 9 153. 4 36 {Control 0 55. 3 7. 8 27. 4 lifl-benzyloxy-N--"-estratr1cnc-3-one 2 50. 1 25. 7 29. 5 10 83. 2 41. 3 24. 7 10 {C ro 0 42. s 7. 2 11. n 17fi-eyelohexylmethoxy-A- cstratriene-3-one 10 100. 7 57.0 38. 7 2i {Control 1. 0 41. 4 9. 3 10. 4 l7fi-cyclohexylmethoxy-A -ostratriene-(i-one 10 168. 2 69. 0 25. 6 38 {Con 0 51. 9 5.1 9. 6 17fl-cyclohexyImethoxy-N -cstratricne-B-one 10 184. 8 94. 1 33. 5 10 {Control 0 43. 3 8.0 11.2 l7B-eyclohexylmethoxy-A -cstratriene-Ei-one 2 84. 8 23. 2 21. 0 24 {Control 1 0 40. 4 7. 1 11. 1 2 105. 6 27. 2 1!). 1 3S 0 49. 5 7. 1 12.8 2 92. 1 19. 1 17. 0

7 {Control 0 52. 7 9. 6 8. 1 704411051131147B-b011ZylOXy-A -CStIEllZl'lGIlG-i3-011O-. 10 92. 7 91. 2 96. 5 21 {Control 0 46. 3 6. 9 6. 4 7a-n1etl1y1 17fl benzyloxy-N- -estratrione-30ne 10 115. 2 250. 0 187. 8 35 Control 0 73. 9 7. 5 6. 5 'l7a-metliyl-l7fi-benzyloxy-A -0 estratrlene-Zi-ono. 10 160. 1 206. 0 443. 0

These results demonstrate the persistency of the androgenic and anabolic efifect of the compounds studied over long periods of time after a single injection at the dosages indicated.

(B) Study of the storage of androgenic steroids in the rat (1) In the zone of injection at various times after administration in oily solution.

(2) Products studied:

Technique The zone surrounding the point of injection is separated borhood of that of the product administered. The evaluation figures, with reference to those of the zone of injection, are based on a correction by readings of the two (420 and 340 m With the chromatograph, subsequently the examination of the plates at 366 mp. (fluorescent 3-keto trienic structure) allows the qualitative verification of the preceding results and authenticates the presence of the products. The sensitivity is superior to that obtained with a spectrophotometer.

Remarks With reference to the zones of injection, it is quite evident that the precision of the sampling is a function of time elapsed since the treatment. During the first days, the oily solvent is quite localized and the sampling is easily definable. In contrast, after more prolonged times, a large diffusion is produced and the limits of the sampling become imprecise; the evaluations are, therefore, partially a function of the surface sampled.

The results shown in the table are of products found in the region injected subcutaneously in solution in olive oil containing 5% of benzyl alcohol. The products studied were administered in the dosages indicated.

The animals utilized are castrated male rats as utilized in (A) above in the Sakamoto test.

Table VII below gives the results obtained. The underlined value in the column Evaluation as percent of the dose injected is the average for the values obtained from the individual rats.

TABLE VII Storage at the Point of Injection Spectra Day of Number of m Chroma- Dose administered, mg. sacrifice animals otamax. the dose in ected tography ducts tudied: 1581f 10 5 5 0 0 Trace 3 out or 5. 10 12 5 0 0 Traccsl out 015.

2,951. 10 7 Pool 13.0 10 21 5 0.1; 28.4;0.5; 9.5; 13.8

TABLE VIICntinucd Spectra.

Evaluation as persupplemental treatment as a cicatrization agent in the treatment of varicose ulcers.

The 17fl-cyclic ethers of the A -gonatrienes, corresponding with the general Formula I, are utilized preferably by administration in an oily solution, transcutaneous- 1y. They can be prepared in the form of injectable solutions or suspensions, in the form of solutions for transcutaneous usage.

The useful dosology is controlled between 15 mg./kg. and 100 mg./kg. in the warm-blooded animal according to the product utilized and as a function of the frequency of administration and therapeutic indication.

The pharmaceutical forms such as injectable solutions or suspensions and solutions for the transcutaneous usage, are prepared according to the usual processes or as indicated in the preceding examples.

The preceding specific embodiments are illustrative of the invention. It is to be understood, however, that other expedients known to those skilled in the art may be employed without departing from the spirit of the invention.

Dose admin- Day of Number of Presence cent of the dose Chromaistered, mg. sacrifice animals of a max. injected tography Average 10.5

38 Pool 1.0

4,442 10 7 Pool 19.3

Average 10.5

These results demonstrate that the alcohol, 17a-methyl- We claim: A -estratriene-17}8-ol-3-one (1881) does not persist at 1. A -gonatrienes of the formula the zone of injection and has almost completely disappeared five days after the injection. In contrast, the 17pcyclic ethers of the invention are present at the zone of injection in relatively large amounts of from 13% to R OCHFR 19.3% of the dosage injected after one week and for periods of over thirty days, measurable amounts of the injected steroid may be found. As shown in Table VII, these 17fi-cyclic ethers of the invention are eifective as androgenic and anabolisant agents over this entire period of over thirty days. Of the compounds tested, 17fl-cyclo- A- R1 hexylmethoxy-A -estradiene 3 one (3785) and 7amethyl-17fi-benzyloxy-A -estratriene 3 one (4442) were equivalent and showed the longest persistency of eflectiveness. wherein As it has been already indicated, the 17 3-cyclic ether A represents a member Selected from the group C011- compounds of the general Formula I are endowed with SIFtmg of y dl-lowef-alkoxy and lower alkylene interesting pharmacological properties. In particular, they Y; possess an important anabolisant and androgenic action R represents an alkyl haVlIlg from 1 t0 4 Carbon atoms; of a persistent nature. They can be utilized for the treat- 1 fepresents a member Selected from the group c011 merit of disturbances of proteidic anabolism, of asthenia, slstlng of hydrogen and lower lkyl; and of thinness, osteoporosis, andropause, senescence, re- 2 FePTeSentS a member Selected from the group tarded consolidation of fractures, metabolic disturbances slstmg of p y IOWBT alkylsulfonylphenyl, lower due to prolonged cortico therapy, adiposogenital synylph nyl, halophenyl, lower 9 yp y y drome, functional meno-metrorrhagia, fibroma, endomeheXyl, cycloheXeIlyl y q y triosis. Furthermore, the compounds can be utilized for The compound Of 01mm 1 Wherem A is oxygen, R

is methyl, R is hydrogen and R is phenyl.

3. The compound of claim 1 wherein A is oxygen, R is ethyl, R is hydrogen and R is phenyl.

4. The compound of claim 1 wherein A is oxygen, R is methyl, R is methyl and R is phenyl.

5. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is p-methylsulfonylphenyl.

6. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is 2,4,6-trimethylphenyl.

7. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is cyclohexyl.

8. The compound of claim 1 wherein A is ethylenedioxy, R is methyl, R is hydrogen and R is phenyl.

9. The compound of claim 1 wherein A is ethylenedioxy, R is methyl, R is hydrogen and R is p-methylsulfonylphenyl.

10. The compound of claim 1 wherein A is ethylenedioxy, R is methyl, R is hydrogen and R is 2,4,6-trimethylphenyl.

11. The compound of claim 1 wherein A is ethylenedioxy, R is ethyl, R is hydrogen and R is phenyl.

12. The compound of claim 1 wherein A is ethylenedioxy, R is methyl, R is hydrogen and R is cyclohexyl.

13. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is p-chlorophenyl.

14. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is p-methoxyphenyl.

15. The compound of claim 1 wherein A is oxygen, R is methyl, R is hydrogen and R is cyclohex-l-enyl.

16. 17fl-cyclic ethers of A -gonatrienes of the formula R o-om-m 20 wherein A represents a member selected from the group consisting of oxygen and lower alkylene dioxy;

R represents alkyl having from 1 to 4 carbon atoms;

R represents a member selected from the group consisting of phenyl, lower alkylsulfonylphenyl, lower alkylphenyl, halophenyl, lower alkoxyphenyl, cyclohexyl and cycle hexenyl; and

R represents a member selected from the group consisting of hydrogen and methyl.

References Cited UNITED STATES PATENTS 3,052,672 9/ 1962 Nomine et al.

3,086,027 4/1963 Perelman et al.

3,453,267 7/1969 Vignau et al.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 

